Apolipoprotein L1 Opinions of African American Living Kidney Donors, Kidney Transplant Patients, and Nonpatients.

INTRODUCTION: The discovery of apolipoprotein L1 (ApoL1) has raised important ethical and clinical questions about genetic testing in the context of living and deceased kidney donation. Largely missing from this discussion are the perspectives of those African Americans (AA) most likely to be impacted by ApoL1 testing. METHODS: We surveyed 331 AA potential and former living kidney donors (LKDs), kidney transplant candidates and recipients, and nonpatients at three United States transplant programs about their ApoL1 testing attitudes. RESULTS: Overall, 72% felt that transplant programs should offer ApoL1 testing to AA potential LKDs. If a potential LKD has the high-risk genotype, 79% felt that the LKD should be allowed to make their own donation decision or participate in shared decision-making with transplant doctors. More than half of the potential LKDs (58%) would undergo ApoL1 testing and 81% of former LKDs would take the test now if offered. Most transplant candidates expressed a low likelihood of accepting a kidney from a LKD (79%) or a deceased donor (67%) with the high-risk genotype. CONCLUSIONS: There is strong support among LKDs and transplant patients for ApoL1 testing when evaluating potential kidney donors of African ancestry. Inclusion of AA stakeholders in developing guidelines and educational programs for ApoL1 testing is critical.

Chronic Kidney Disease Burden in Low-Resource Settings: Regional Perspectives.

The burden of chronic kidney disease (CKD) has increased exponentially worldwide but more so in low- and middle-income countries. Specific risk factors in these regions expose their populations to an increased risk of CKD, such as genetic risk with APOL1 among populations of West African heritage or farmers with CKD of unknown etiology that spans various countries across several continents to immigrant/indigenous populations in both low- and high-income countries. Low- and middle-income economies also have the double burden of communicable and noncommunicable diseases, both contributing to the high prevalence of CKD. The economies are characterized by low health expenditure, sparse or nonexistent health insurance and welfare programs, and predominant out-of-pocket spending for medical care. This review highlights the challenges in populations with CKD from low-resource settings globally and explores how health systems can help ameliorate the CKD burden.

APOL1 renal risk variants are associated with obesity and body composition in African ancestry adults: An observational genotype-phenotype association study.

ABSTRACT: While increased obesity prevalence among persons of African ancestry (AAs) compared to persons of European ancestry (EAs) is linked to social, environmental and behavioral factors, there are no gene variants that are common and significantly associated with obesity in AA populations. We sought to explore the association between ancestry specific renal risk variants in the apolipoprotein L1 (APOL1) gene with obesity related traits in AAs.We conducted a genotype-phenotype association study from 3 electronic medical record linked cohorts (BioMe Biobank, BioVU, nuGENE); randomized controlled trials (genetic testing to understand and address renal disease disparities) and prospective cohort study (Jackson Heart Study). We analyzed association of APOL1 renal risk variants with cross-sectional measures of obesity (average body mass index (BMI), and proportion of overweight and obesity) and with measures of body composition (in Jackson Heart Study).We had data on 11,930 self-reported AA adults. Across cohorts, mean age was from 42 to 49 years and percentage female from 58% to 75.3%. Individuals who have 2 APOL1 risk alleles (14% of AAs) have 30% higher obesity odds compared to others (recessive model adjusted odds ratio 1.30; 95% confidence interval 1.16-1.41; P = 2.75 × 10-6). An additive model better fit the association, in which each allele (47% of AAs) increases obesity odds by 1.13-fold (adjusted odds ratio 1.13; 95% confidence interval 1.07-1.19; P = 3.07 × 10-6) and increases BMI by 0.36 kg/m2 (∼1 kg, for 1.7 m height; P = 2 × 10-4). APOL1 alleles are not associated with refined body composition traits overall but are significantly associated with fat free mass index in women [0.30 kg/m2 increment per allele; P = .03].Thus, renal risk variants in the APOL1 gene, found in nearly half of AAs, are associated with BMI and obesity in an additive manner. These variants could, either on their own or interacting with environmental factors, explain a proportion of ethnic disparities in obesity.

Quality over quantity: A qualitative, targeted bottom-up proteomics approach to genotyping apolipoprotein L1.

A targeted, bottom-up proteomic assay was developed for the qualitative detection of apolipoprotein L1 (ApoL1) protein variants (G0, G1, and G2) in blood plasma for identification of high and low renal risk genotypes. Following trypsin digestion of liquid or dry plasma, surrogate peptides specific to each ApoL1 variant were detected by liquid chromatography-tandem mass spectrometry along with two surrogate peptides common among all variants which served as internal (positive) controls to verify correct sample processing. Using isotopically labeled peptide internal standards, the presence or absence of each surrogate peptide was determined using multiple objective metrics including: 1) retention time confirmation relative to its internal standard, 2) comparison of the internal standard-normalized response relative to pre-established thresholds for confident detection, and 3) ion ratio monitoring. Based on the pattern of variant-specific surrogate peptides detected, the genotype was accurately inferred. The final, optimized method was fully validated for liquid plasma specimens, as well as dry plasma specimens collected on a laminar flow blood separation device. For both specimen types, the latter which can be self-collected for remote or in-home sampling, the assay was shown to be reproducible, interference-free with the exception of gross hemolysis, and accurate relative to Sanger sequencing (100% agreement). This targeted, qualitative bottom-up proteomic assay for detection of ApoL1 variants in blood provides a high-throughput, cost-effective alternative to molecular methods and has potential implications to improve organ allocation by facilitating screening kidney donors for high-risk ApoL1 genotypes, but could be applicable for genotyping other clinically relevant blood proteins variants.

APOL1 Genotyping in Potential African American Living Kidney Donors: Utility and Cost-Effectiveness.

BACKGROUND: Apolipoprotein L1 gene (APOL1) variants predispose to nondiabetic kidney disease in African American (AA) patients. Here, we share our experience with APOL1 genotyping of AA potential living kidney donors and offer a perspective on its utility and cost-effectiveness in this population. METHODS: Since May 2017, all potential AA living kidney donors at our center underwent APOL1 genotyping early in the donor evaluation process. APOL1 high-risk individuals were declined, whereas those with low-risk genotype continued with further evaluation and testing. RESULTS: One out of 26 potential donors had high-risk genotype and was therefore declined. The rest were eligible to continue the donor evaluation process and 7 of them underwent donor nephrectomy without any complications. A crude cost analysis utilizing our sample suggested probable cost-effectiveness of APOL1 genotyping as it can prevent earlier onset of chronic kidney disease in AA donors. CONCLUSION: We propose a role for systematically incorporating APOL1 genotyping in the evaluation and informed consent process of potential AA donors while acknowledging the controversial considerations associated with it.

Genetics and ESKD Disparities in African Americans.

African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.

Apolipoprotein L1 Testing in African Americans: Involving the Community in Policy Discussions.

BACKGROUND: Apolipoprotein A1 (APOL1) gene variants occurring in people of West African descent contribute to the greater burden of kidney disease among African Americans. These variants are associated with increased risk of nondiabetic nephropathy, more rapid progression of chronic kidney disease, and shorter survival of donor kidneys after transplantation. However, only a minority of people with APOL1-associated risk develops kidney disease and specific clinical measures to address APOL1-associated risk are lacking. Given these uncertainties, we sought to engage members of the African American public in discussions with other stakeholders about the appropriate use of APOL1 testing. METHODS: Formative interviews with community members, researchers, and clinicians in Seattle WA, Nashville TN, and Jackson MS, provided baseline information about views toward APOL1 testing and informed the design of 3 community-based deliberations among African Americans. A national meeting held in March 2018 included 13 community members, 7 scientific advisors and 26 additional researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and federal funding agencies. Using small break-out and plenary discussion, the group agreed on recommendations based on current knowledge about APOL1-associated risk. RESULTS: Meeting outcomes included recommendations to develop educational materials about APOL1 for community members and clinicians; to offer APOL1 research results to participants; and on the use of APOL1testing in kidney transplant programs. The group recommended against the routine offer of APOL1 testing in clinical care. Areas of disagreement included whether kidney transplant programs should require APOL1 testing of prospective living donors or bar individuals with APOL1 risk from donating kidneys and whether testing should be available on request in routine clinical care. CONCLUSION: We recommend continued discussion among stakeholders and concerted efforts to ensure active and informed participation of members of the affected community to guide research on APOL1 and kidney disease.

A Focus Group Study on African American Living Donors' Treatment Preferences, Sociocultural Factors, and Health Beliefs About Apolipoprotein L1 Genetic Testing.

INTRODUCTION: Because apolipoprotein L1 (APOL1) risk variants may contribute to live donors' kidney failure postdonation, professional guidelines suggest informing potential donors with African ancestry about the availability of APOL1 genotyping. This study assessed African American (AA) donors' perceptions of APOL1 genetic testing and how APOL1 may affect ethnic identity. METHODS/APPROACH: Four focus groups were conducted with AA donors about their decision-making for and perceptions of APOL1 genetic testing and donation to inform a new culturally targeted educational brochure on APOL1 genetic testing. Qualitative data were analyzed by thematic analysis. FINDINGS: Seventeen donors participated (47% participation rate). Four major themes emerged. (1) In hypothetical scenarios, most participants would have undergone APOL1 testing during donor evaluation to make a more informed decision, but many would have still donated. (2) Participants desired information about how having 2 APOL1 risk variants affects the donor's and the recipient's health. (3) Participants referred to diversity of genetic ancestry and cultural constructions of racial/ethnic identity to question the population at risk for APOL1 risk variants and recommended that all potential donors undergo genetic testing and receive education about APOL1. (4) Participants worried that out-of-pocket costs would deter APOL1 testing and that APOL1 could become a preexisting condition and discriminate against AAs. DISCUSSION: Our findings suggest that AA donors desire APOL1 testing to foster informed consent. Transplant clinicians should be aware of these responses to APOL1 testing and be sensitive to historical issues of distrust and discrimination.

A National Survey of Transplant Surgeons and Nephrologists on Implementing Apolipoprotein L1 (APOL1) Genetic Testing Into Clinical Practice.

INTRODUCTION: There is debate over whether Apolipoprotein L1 (APOL1) gene risk variants contribute to African American (AA) live donors' (LD) increased risk of kidney failure. Little is known about factors influencing physicians' integration of APOL1 genetic testing of AA LDs into donor evaluation. DESIGN: We conducted a cross-sectional survey, informed by Roger's Diffusion of Innovations theory, among nephrology and surgeon members of the American Society of Nephrology, American Society of Transplantation, and American Society of Transplant Surgeons about their practices of and attitudes about APOL1 genetic testing of AA potential LDs. Descriptive statistics and bivariate analyses were performed. RESULTS: Of 383 completed surveys, most physicians believed that APOL1 testing can help AA LDs make more informed donation decisions (87%), and the addition of APOL1 testing offers better clinical information about AA LD's eligibility for donation than existing evaluation approaches (74%). Among respondents who evaluate LDs (n = 345), 63% would definitely or probably begin or continue using APOL1 testing in the next year, however, few use APOL1 testing routinely (4%) or on a case-by-case basis (14%). Most did not know the right clinical scenario to order APOL1 testing (59%), but would use educational materials to counsel AA LDs about APOL1 testing (97%). DISCUSSION: Although physicians were highly supportive of APOL1 genetic testing for AA LDs, few physicians use APOL1 testing. As more physicians intend to use APOL1 testing, an ethical framework and clinical decision support are needed presently to assist clinicians in clarifying the proper indication of APOL1 genetic testing.

African American Living Donors' Attitudes About APOL1 Genetic Testing: A Mixed Methods Study.

RATIONALE & OBJECTIVE: African American live kidney donors ("donors") have a greater risk for kidney failure than European American donors. Apolipoprotein L1 gene (APOL1) variants in African Americans may be associated with this disparity. STUDY DESIGN: Cross-sectional mixed-methods design. SETTING & PARTICIPANTS: African American donors at 1 transplantation center. ANALYTICAL APPROACH: Semistructured interviews assessed attitudes about APOL1 genetic testing, willingness to undergo APOL1 testing, hypothetical decisions about donating with 2 APOL1 variants, and demographics. Surveys assessed perceptions of ethnic identity and genetics knowledge. Interview transcriptions were analyzed using thematic analysis. Survey data were analyzed using descriptive statistics. RESULTS: 23 donors participated in semistructured interviews. Most (96%) reported that transplantation centers should routinely offer APOL1 genetic testing to all African American potential donors. Most (87%) would have been willing to undergo APOL1 testing before donating. Although study participants noted that APOL1 testing may deter African American potential donors from donating, most (61%) would have donated even if they had 2 high-risk APOL1 variants. Several themes emerged. Study participants believed that APOL1 testing was beneficial for providing information to help donors make informed donation decisions. Participants expressed concern about APOL1 variants placing donors at harm for kidney failure, and therefore valued taking preventive health measures. Participants believed that potential donors would experience psychological distress from learning that they have 2 gene variants and could harm their recipients. Participants were apprehensive about insurance coverage and costs of APOL1 testing and feared that APOL1 genetic test results could discriminate against African Americans. LIMITATIONS: Findings may not be generalizable to African American potential donors. CONCLUSIONS: Findings suggest that African American donors support APOL1 genetic testing yet fear that APOL1 variants and genetic testing could adversely affect donors' health and ethnic identity. Transplantation centers using APOL1 genetic testing should address African American donors' concerns about APOL1 genetic testing to optimize future donors' informed consent practices.

Apolipoprotein L1 Gene Effects on Kidney Transplantation.

The pathogenesis of many common etiologies of nephropathy has been informed by recent molecular genetic breakthroughs. It now is apparent that the ethnic disparity in the risk for nondiabetic chronic kidney disease between African Americans and European Americans is explained largely by variation in the apolipoprotein L1 gene (APOL1). The presence of two APOL1 renal risk variants markedly increases an individual's risk for kidney disease. In transplantation, kidneys from deceased African Americans with two APOL1 renal risk variants have shorter survival intervals after engraftment, regardless of the ethnicity of the recipient. Precision medicine will transform the clinical practice of nephrology and kidney transplantation, and play an important role in the allocation of kidneys from deceased and living kidney donors with recent African ancestry. This article reviews existing data on APOL1 in deceased-donor and living-donor kidney transplantation. It considers the impact of including APOL1 genotyping in decisions on the allocation and discard of deceased-donor kidneys, as well as the selection of living donors.

Current State and Future Trends to Optimize the Care of Chronic Kidney Disease in African Americans.

BACKGROUND: African Americans (AAs) suffer the widest gaps in chronic kidney disease (CKD) outcomes compared to Caucasian Americans (CAs) and this is because of the disparities that exist in both health and healthcare. In fact, the prevalence of CKD is 3.5 times higher in AAs compared to CAs. The disparities exist at all stages of CKD. Importantly, AAs are 10 times more likely to develop hypertension-related kidney failure and 3 times more likely to progress to kidney failure compared to CAs. SUMMARY: Several factors contribute to these disparities including genetic and social determinants, late referrals, poor care coordination, medication adherence, and low recruitment in clinical trials. Key Messages: The development and implementation of CKD-related evidence-based approaches, such as clinical and social determinant assessment tools for medical interventions, more widespread outreach programs, strategies to improve medication adherence, safe and effective pharmacological treatments to control or eliminate CKD, as well as the use of health information technology, and patient-engagement programs for improved CKD outcomes may help to positively impact these disparities among AAs.

The African diaspora: history, adaptation and health.

The trans-Atlantic slave trade brought millions of Africans to the New World. Advances in genomics are providing novel insights into the history and health of Africans and the diasporan populations. Recent examples reviewed here include the unraveling of substantial hunter-gatherer and 'Eurasian' admixtures across sub-Saharan Africa, expanding our understanding of ancestral African genetics; the global ubiquity of mixed ancestry; the revealing of African ancestry in Latin Americans that likely derived from the slave trade; and understanding of the ancestral backgrounds of APOL1 and LPL found to influence kidney disease and lipid levels, respectively, providing specific insights into disease etiology and health disparities.